The invention relates to chemical compounds and pharmaceutical compositions, including novel chemical compounds and pharmaceutical compositions thereof, useful in the treatment of various diseases and disease states. The invention also relates to methods of synthesizing natural products and novel, structurally-related chemical compounds. More particularly, the present invention relates to novel analogs of and processes for the preparation of compounds and pharmaceutical compositions thereof useful in the treatment of, for example, inflammation, cancer, cachexia, cardiovascular disease, diabetes, otitis media, sinusitis and transplant rejection.
Acanthopanax koreanum Nakai (Araliaceae), which is found indigenously in Cheju Island, The Republic of Korea, has been used traditionally as a remedy for, for example, neuralgia, paralysis, and lumbago. Various useful components, including acanthoic acid, a compound having the chemical structure of Formula (I), have been isolated from the root bark of this tree. Furthermore, certain analogs of the compound of Formula (I), for example, wherein the COOH group is replaced by a methanolic group, by a methyl-acetyl ether, by a methyl group, and by a methyl-ester have each also been isolated from the root bark of Acanthopanax koreanum Nakai (Araliaceae). See Kim, Y. H. and Chung, B. S., J. Nat. Pro., 51, 1080-83 (1988). (The proper chemical names of these analogs are provided in this reference.) This reference and all the other patents and printed publication cited herein are, in their entirety, incorporated by reference herein. 
The compound of Formula (I), also known as acanthoic acid, has been reported to have certain pharmacological effects, including, for example, analgesic and anti-inflammatory activity. The compound of Formula (I) also exhibits very low toxicity; 1000 mg/kg is the minimum lethal dose (MLD) when administered to a rat. See Lee, Y. S., xe2x80x9cPharmacological Study for (xe2x88x92)-Pimara-9(11),15-Diene-19-oic Acid, A Component of Acanthopanax koreanum Nakai,xe2x80x9d Doctorate Thesis, Dept. of Pharmacy, Seoul National University, Korea (1990). The compound of Formula (I) and/or its naturally-occurring analogs, may exhibit these known pharmacological effects by inhibiting leukocyte migration and prostaglandin E2(PGE2) synthesis, and is a suspected effector of both Interleukin-1 (IL-1) and Tumor Necrosis Factor-xcex1 (TNF-xcex1) production. Additionally, a process for the preparation of acanthoic acid, and use of the acanthoic acid for treatment of immune disease is described in International Patent Publication WO 95/34300 (Dec. 21, 1995).
Also, the compound of Formula (IA), kauranoic acid, and the corresponding methyl-ester analog of the compound of Formula (IA), as well as methanolic reduction analogs of the compound of Formula (IA) have been isolated from the root bark of Acanthopanax koreanum Nakai (Araliaceae). See Kim, Y. H. and Chung, B. S., J. Nat. Pro., 51, 1080 (1988). (The proper chemical name of kauranoic acid, (xe2x88x92)-kaur-16-en-19-oic acid, and of the known analogs of kauranoic acid are provided in this reference.) 
Tumor Necrosis Factor-xcex1 (herein xe2x80x9cTNF-xcex1xe2x80x9d or xe2x80x9cTNFxe2x80x9d) and/or Interleukin-1 (herein xe2x80x9cIL-1xe2x80x9d) are involved in various biochemical pathways and, thus modulators of TNF-xcex1 and/or IL-1 activity or production, especially novel modulators of TNF-xcex1 and/or IL-1 activity or novel compounds that influence the production of either IL-1 or TNF-xcex1, or both, are highly desired. Such compounds and classes of compounds would be valuable in maintaining the human immune system and in treating diseases such as for example, tuberculous pleurisy, rheumatoid pleurisy, and diseases not conventionally considered to be immune disorders, such as cancer, cardiovascular disease, skin redness, viral infection, diabetes, and transplant rejection.
Although numerous approaches to regulate the production of Tumor Necrosis Factor-xcex1 and the interleukins are known, novel approaches, compounds, and pharmaceutical formulations to regulate the production of Tumor Necrosis Factor-xcex1 and interleukins are highly desirable and have been long sought by those of skill in the art.
Accordingly, it is an object of the present invention to provide processes for the synthetic and semi-synthetic preparation of the compounds of Formulae (I) and (IA) and their structural analogs, including novel analogs, of the compounds of Formulae (I) and (IA).
The compounds of the present invention include, for example, compounds having the chemical structure of Formula (II) and compounds having the chemical structure of Formula (IIA). Regarding compounds having the chemical structure of Formula (II), the invention includes: 
wherein the R groups are defined as follows: If any R3-R5, R7, R8, R11-R13 is not hydrogen, R2 or R6 or R9 is not methyl, or R10 is not CH2, then R1 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12)(C1-C12) tertiary amides, C1-C12 alcohols, (C1-C12)(C1C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls, and C5-C12 aryls; however, if all R3-R5, R7, R8, R11-R13 are hydrogen, R2, R6, and R9 are each methyl, and R10 is CH2, then R1 is selected from hydrogen, a halogen, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C2-C12 esters, C2-C12 secondary amides, (C1-C12)(C1-C12) tertiary amides, C2-C12 alcohols, (C1-C12)(C1-C12) ethers other than methyl-acetyl ether, C2-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls, and C2-C12 aryls.
R2 and R9 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 acyl, C1-C12 alcohol, and C5-C12 aryl.
R3-R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, and C5-C12 aryl. In particularly preferred embodiments, R11 is a C1-C6 alkyl, or C1-C6 substituted alkyl, and all other R groups are hydrogen.
R6 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, and C2-C12 alkynyl.
R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and C5-C12 aryl.
R14 and R15 are separately selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, and C5-C6 aryl.
Regarding compounds having the chemical structure of Formula (IIA), the invention includes: 
wherein, if any R3-R5, R7, R8, R11-R13 is not hydrogen, R2 or R6 is not methyl, R10 is not CH2, or if it is not true that R10 is CH2OH and R11 is OH, then R1 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1C12 secondary amides, (C1-C12)(C1-C12) tertiary amides, C1-C12 alcohols, (C1-C12)(C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls; but
if all R3-R5, R7, R8, R11-R13 are hydrogen, R2 and R6 are each methyl, and R10 is CH2 or CH2OH, then R1 is selected from hydrogen, a halogen, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C2-C12 esters, C1-C12 secondary amides, (C1-C12)(C1-C12) tertiary amides, C2-C12 alcohols, (C1-C12)(C1-C12) ethers, C2-C12 alkyls, C2-C12 substituted alkyls, C2-C12 alkenyl, and C2-C12 substituted alkenyl;
R2 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 acyl, C1-C12 alcohol, and C5-C12 aryl;
R3, R4, R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, and C5-C12 aryl. In particularly preferred embodiments, R11 is a C1-C6 alkyl, or C1-C6 substituted alkyl, and all other R groups are hydrogen;
R6 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, and C2-C12 alkynyl;
R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and C5-C12 aryl; and
R14 and R15 may be stereo-specific, and are separately selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, and C5-C6 aryl.
It is a further object of the invention to provide compounds having the chemical structure of Formula (IIB), and to provide processes for the synthetic and semi-synthetic preparation of compounds having the chemical structure of Formula (IIB). Regarding said compounds having the chemical structure of Formula (IIB), for example, the compounds herein designated TTL1, TTL2, TTL3, TTL4, and their analogs and derivatives, the invention includes: 
wherein the R groups are defined as follows: R1 is selected from the group consisting of hydrogen, a halogen, COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, C1-C12 esters, C1-C12 secondary amides, (C1-C12)(C1-C12) tertiary amides, C1-C12 alcohols, (C1-C12)(C1-C12) ethers, C1-C12 alkyls, C1-C12 substituted alkyls, C2-C12 alkenyls, C2-C12 substituted alkenyls, and C5-C12 aryls. Under these conditions, R1 is preferably selected from COOH, C1-C12 carboxylic acids, C1-C12 acyl halides, C1-C12 acyl residues, and C1-C12 esters, and is most preferably selected from COOH and the C1-C6 esters.
R2 and R9 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, C1-C12 acyl, C1-C12 alcohol, and C5-C12 aryl.
R3-R5, R7, R8, and R11-R13 are each separately selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, and C5-C12 aryl. In particularly preferred embodiments, R11 is a C1-C6 alkyl, or C1-C6 substituted alkyl, and all other R groups are hydrogen.
R6 is selected from hydrogen, a halogen, C1-C12 alkyl, C1-C12 substituted alkyls, C2-C12 alkenyl, C2-C12 substituted alkenyl, and C2-C12 alkynyl.
R10 is selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C12 alcohol, and C5-C12 aryl.
R14 and R15 are stereo-specific and are separately selected from hydrogen, a halogen, CH2, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C1-C6 alcohol, and C5-C6 aryl.
It also will be appreciated that the various R groups, most particularly R3, R4, R5, R7, R8, and R11 -R13, may be chosen such that cyclic system are formed. For example, both R13 and R12 may be ethylene moieties and may include a covalent Cxe2x80x94C linkage between their respective terminal carbons, generating an additional six-membered ring in the compound of Formula (IIB). As a further example, bis-cyclic rings may be formed by choosing appropriate chemical species for the various R groups, most particularly R3, R4, R5, R7, R8, and R11-R13 of Formula (IIB).
The compounds of the invention include the prodrug esters of the compounds of Formulae (II), (IIA), and (IIB), and the acid-addition salts of the compounds of Formulae (II), (IIA), and (IIB), and pharmaceutical compositions comprising a therapeutically effective amount of the described compounds, including their prodrug esters and their acid-addition salts, optionally in conjunction with a pharmaceutically acceptable carrier. Such compositions are useful as, for example, anti-inflammatory analgesics, in the treatment of immune and auto-immune disorders, as anti-cancer or anti-tumor agents, and are useful in the treatment of cardiovascular disease, skin redness, viral infection, diabetes, otitis media, sinusitis and/or transplant rejection. Particularly, a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulae (II), (IIA), or (IIB), or a pro-drug ester and acid addition salt of a compound of Formulae (II), (IIA), or (IIB), may be used as an anti-cancer, anti-tumor agent, anti-viral agent, and may be useful in the treatment of cardiovascular disease, skin redness, viral infection, , diabetes, otitis media, sinusitis and/or transplant rejection.
The invention also provides novel methods of synthesizing the above described compounds and their analogs comprising the step of performing a Diels-Alder reaction reacting a diene having two or more rings with a dienophile compound to yield a resultant compound have three of more rings; and yielding a desired synthetic compound. The Diels-Alder reaction, along with the selection of the diene and the dienophile affords flexibility in synthesizing a variety of compounds of the invention, and allows for the use of combinatorial chemistry libraries of compounds of the invention, for use biological assays, including clinical trials.